Abstract: Neurogenic inflammation results from magnesium deficiency (MgD), and is mediated by Substance P (SP). Neutral endopeptidase (NEP) is the principal proteolytic SP degrading enzyme, and alterations in NEP activity may determine the severity of SP- mediated inflammation affecting cardiac and intestinal tissues. Recently, using echocardiography, we observed cardiac systolic and diastolic dysfunction in MgD rodents. Also, cardiac dysfunction occurred at the time when circulating endotoxin was significantly elevated. To pursue the mechanisms leading to the role of SP in this cardiac pathology, we propose to: 1. Determine the contribution of NEP to SP-mediated inflammation and oxidative stress leading to cardiac dysfunction during MgD in the rat. 2 Confirm the importance of NEP status in SP-mediated inflammation and associated endotoxemia in the development of cardiac dysfunction during MgD, by using genetically manipulated murine models [NEP(-/-) and CD14 (-/-) mice]. 3. Determine if cardiac dysfunction/failure mediated by the anticancer drug, doxorubicin (DOX), is enhanced by SP-mediated inflammation and associated endotoxemia during MgD. The high incidence of hypomagnesemia in cancer patients may result in enhanced cardiac susceptibility to the iron dependent pro-oxidant effects of DOX. We anticipate that our studies will shed new light on SP-mediated cardiomyopathy and the possible role of MgD as a risk factor for delayed cardiac toxicity that occurs in pediatric and adult cancer patients from prior treatment with DOX.